Organocatalyst-mediated enantioselective intramolecular aldol reaction featuring the rare combination of aldehyde as nucleophile and ketone as electrophile

Article abstract of DOI:10.1021/jo0709100

(Chemical Equation Presented) The trifluoroacetic acid salt of 2-(pyrrolidinylmethyl)pyrrolidine was found to be an effective organocatalyst of an asymmetric intramolecular aldol reaction, affording bicyclo[4.3.0]nonane derivatives with a high enantiosele

Full text of DOI:10.1021/jo0709100

Organocatalyst-Mediated Enantioselective Intramolecular Aldol
Reaction Featuring the Rare Combination of Aldehyde as
Nucleophile and Ketone as Electrophile
Yujiro Hayashi,* Hiromi Sekizawa, Junichiro Yamaguchi, and Hiroaki Gotoh
Department of Industrial Chemistry, Faculty of Engineering, Tokyo UniVersity of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
hayashi@ci.kagu.tus.ac.jp
ReceiVed May 9, 2007
The trifluoroacetic acid salt of 2-(pyrrolidinylmethyl)pyrrolidine was found to be an effective organocatalyst
of an asymmetric intramolecular aldol reaction, affording bicyclo[4.3.0]nonane derivatives with a high
enantioselectivity, in which the rare combination of aldehyde as a nucleophile and ketone as an electrophile
was realized.
Introduction
siloxyproline ammonium salt for the synthesis of bicyclo[3.3.1]-
alkanones (eq 3)6a and applied this reaction to the total synthesis
of (-)-CP55,940.6b
The intramolecular aldol reaction is a powerful method for
the synthesis of cyclic carbocycles. In the early 1970s, Hajos
and Parrish and Eder et al. discovered a proline-catalyzed
asymmetric intramolecular aldol reaction of triketones, which
afforded synthetically useful bicyclic compounds in good yield
with excellent enantioselectivity (eq 1).1
In 2000, List et al. disclosed a proline-mediated asymmetric
and direct intermolecular aldol reaction.2 Since this discovery,
many kinds of organocatalysts have been developed for
intermolecular aldol reactions.3,4 Regarding intramolecular aldol
reactions, List and co-workers reported a dienal system for the
synthesis of chiral cyclohexanecarbaldehydes catalyzed by
proline in excellent enantioselectivity (eq 2).5 Iwabuchi and co-
workers reported an intramolecular aldol reaction catalyzed by
* Corresponding author. Fax: (+81)3-5261-4631; tel.: (+81)3-5228-8318.
(1) (a) Hajos, Z. G.; Parrish, D. R. German Patent 2,102,623, 1971. (b)
Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. (c) Eder, U.;
Sauer, G.; Wiechert, R. German Patent 2,014,757, 1971. (d) Eder, U.; Sauer,
G.; Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496. (e) Barbas and Bui
reported that amine 25 promoted Robinson annulation, but the enantiose-
lectivity is not reported, see: Bui, T.; Barbas, C. F., III. Tetrahedron Lett.
2000, 41, 6951.
(2) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am.
Chem. Soc. 2001, 123, 5260.
(3) (a) List, B. Tetrahedron 2002, 58, 5573. (b) Alcaide, B.; Almendros,
P. Angew. Chem., Int. Ed. 2003, 42, 858. (c) List, B. Modern Aldol
Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; Vol. 1, Ch.
4, pp 161-201. (d) List, B. Acc. Chem. Res. 2004, 37, 548.
In general, aldehydes are more reactive than ketones as
electrophiles. Thus, in most direct asymmetric aldol reactions
catalyzed by organocatalysts, an aldehyde or ketone is used as
the donor, and an aldehyde is used as the acceptor. The reverse
combination, in which an aldehyde is used as the donor and a
ketone is employed as the acceptor, is very rare. One example
is the aldol reaction of aldehyde and activated ketones such as
10.1021/jo0709100 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/19/2007
J. Org. Chem. 2007, 72, 6493-6499
6493

Hayashi et al.
SCHEME 1. Synthetic Scheme of Compounds 5, 11, and 19
diethyl ketomalonate.7 Even among previously described in-
tramolecular aldol reactions using organocatalysts, the combina-
tions of donor and acceptor that have been used are almost
exclusively ketone-ketone, aldehyde-aldehyde, or ketone-
aldehyde. The one exception is the proline-catalyzed reaction
of 2-oxo-octanal, which proceeds with excellent enantioselec-
tivity but low diastereoselectivity.5 In this paper, we disclose
an intramolecular, enantioselective, and direct aldol reaction,
in which the aldehyde and ketone act as donor and acceptor,
respectively.
Results and Discussion
Syntheses of the Starting Materials. 2-(3-Formylpropyl)-
2-methylcyclohexan-1,3-dione (5) was synthesized as follows:
2-methylcyclohexan-1,3-dione (1) was treated with 2-(4-bromo-
2-butenyloxy)tetrahydropyran and NaH in DMF, affording 2
in 86% yield. Hydrogenolysis using Pd/C in MeOH, followed
by removal of the THP group with 1 N HCl and oxidation of
the resulting alcohol 4 with IBX (o-iodoxybenzoic acid) gave
tricarbonyl compound 5.
Similarly, 2-(3-formylpropyl)-2-propylcyclohexan-1,3-dione
(11) was synthesized from cyclohexan-1,3-dione (6) by suc-
cessive alkylation with 2-(4-bromo-2-butenyloxy)tetrahydro-
pyran and allyl bromide, followed by hydrolgenolysis, depro-
tection, and oxidation using IBX.
(4) For reviews on organocatalysis, see: (a) Berkessel, A.; Groger, H.
Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005. (b) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c) Hayashi, Y. J.
Synth. Org. Chem. Jpn. 2005, 63, 464. (d) List, B. Chem. Commun. 2006,
819. (e) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, 2001. (f)
Gaunt, M. J.; Johnsson, C. C. C.; McNally, A.; Vo, N. T. Drug DiscoVery
Today 2007, 12, 8.
2-Benzyloxymethyl-2-(3-formylpropyl)cyclohexan-1,3-di-
one (19) was prepared from 2,6-dimethoxybenzoic acid (12).
Acid 12 was converted into its methyl ester 13. Birch reduction
(5) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem., Int.
Ed. 2003, 42, 2785.
(6) (a) Itagaki, N.; Kimura, M.; Sugahara, T.; Iwabuchi, Y. Org. Lett.
2005, 7, 4185. (b) Itagaki, N.; Sugahara, T.; Iwabuchi, Y. Org. Lett. 2005,
7, 4181.
(7) Bogevig, A.; Kumaragurubaran, N.; Jørgensen, K. A. Chem. Commun.
2002, 620.
6494 J. Org. Chem., Vol. 72, No. 17, 2007

Organocatalyst-Mediated Asymmetric Aldol Reaction
FIGURE 1. Organocatalysts examined in this study.
TABLE 1. Effect of Catalyst in Intramolecular Aldol Reaction
of 5a
TABLE 2. Solvent Effect in Intramolecular Aldol Reactiona
entry
catalyst
20
21
22
23
24
25
25
solvent T (°C) time (h) yield (%)b ee (%)c
34
33
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
NMP
23
23
23
23
23
23
0
8
4
9
63
4
1
94
80
97
-43
-6
5
34
37
3
44
52
45
89
16
21
11
47
24
13
76
entry solvent time (h) yield (%)b ee (%)c yield (%)b ee (%)d
quant.d
quant.d
67
1
2
3
4
5
6e
7
Et2O
3
4
24
0.1
1
42
34
18
33
48
35
<5
66
55
57
63
77
76
nd
32
38
63
38
44
42
96
61
63
61
78
82
85
85
MeOH
CH2Cl2
CH3CN
DMF
NMP
NMP
6
62
25‚HCl
25‚HOTf NMP
NMP
0
3
65
1.5
48
0
0
0
0
0
0
0
0
19
56
40
24
24
24
24
24
24
95
89
53
53
57
56
64
54
25‚TFA
26‚TFA
27‚TFA
28‚TFA
29‚TFA
30‚TFA
31‚TFA
32‚TFA
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
a Reaction was performed employing 5 on a 0.1 to ∼0.15 mmol scale at
0.1 M in each solvent at room temperature. b Isolated yield. c Optical yield
was determined by HPLC on a chiral phase (chiralcel OB-H) after
conversion into dehydrated product 33. d Optical yield was determined by
HPLC on a chiral phase (chiralcel OB-H).
0
56
found to be a suitable solvent (vide infra), the following
experiments were conducted in NMP at 0 °C. Although (S)-2-
(pyrrolidinylmethyl)-pyrrolidine 25 is not an effective catalyst,
its acid salt was found to give good results. Using its HCl salt
improves the enantioselectivity to 52% (Table 1, entry 8).
Although the HOTf salt did not give a better result (45% ee,
Table 1, entry 9), the CF3CO2H salt afforded good enantiose-
lectivity (89% ee, Table 1, entry 10).
As a diamine salt containing a pyrrolidine core had been
found to be an effective catalyst, the effect of altering the “right-
hand” moiety of the diamine as drawn was investigated in detail
as described in Table 1, entries 11-17. Catalysts containing a
secondary amine group (26-28) are not suitable, and neither
are those with a diethyl or dibenzyl amine moiety 29 or 30
effective. The hexamethylene amine 31 is not suitable, while
the catalyst containing a piperidine group 32 gave a good result
(76% ee). It should be noted that Barbas’15 group first reported
that diamine 25 in combined use with CF3CO2H was an effective
organocatalyst of the enantioselective intermolecular aldol
reaction and Michael reaction, while Yamamoto’s16 group
a Reaction was performed employing 5 on a 0.1 to ∼0.15 mmol scale at
0.1 M in each solvent at room temperature or 0 °C. b Isolated yield. c Optical
yield was determined by HPLC on a chiral phase (chiralcel OB-H). d Quant.
) quantitatively.
followed by alkylation with 2-(4-bromobutoxy)tetrahydropyran
afforded 14. Reduction with DIBAL-H and benzyl ether
formation afforded 16. Acid treatment, followed by oxidation,
gave tricarbonyl compound 19.
Screening of the Reaction Conditions. With the starting
materials in hand, the reaction conditions were screened using
tricarbonyl 5 as a model substrate. First, the organocatalyst was
investigated. Tricarbonyl 5 was treated with 30 mol % orga-
nocatalyst in CHCl3 at room temperature. When proline (20)
was used as a catalyst, the aldol reaction proceeded, followed
by the dehydration, affording bicyclo[4.3.0]nonene derivative
33 in 94% yield with 43% ee after 8 h. Several organocatalysts
were employed with the results summarized in Table 1.
Siloxyproline 21, which is an effective catalyst in the R-ami-
noxylation reaction,8 Mannich reaction,8 and aldol reaction in
the presence of water,9 gave a nearly racemic product. Mac-
Millan et al.’s catalyst 2310,11 and diphenylprolinol silyl ether
2412-14 gave the product 33 quantitatively but with low
enantioselectivity. As NMP (N-methyl-2-pyrrolidinone) was
(8) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.; Urushima, T.;
Shoji, M.; Hashizume, D.; Koshino, H. AdV. Synth. Catal. 2004, 346, 1435.
(9) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.;
Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958.
J. Org. Chem, Vol. 72, No. 17, 2007 6495

Hayashi et al.
FIGURE 2. Yields of 5, 33, and 34 vs reaction time.
reported that diamine 25 in combined use with 2,4-dinitroben-
zenesulfonic acid is an effective organocatalyst of the enantio-
selective intermolecular aldol reaction.
Next, the effect of solvent was investigated. As the dehydra-
tion reaction is not so fast when the CF3CO2H salt of 25 is
employed, the aldol product could be isolated. For this screening,
we quenched the reaction after a predetermined time and isolated
both aldol 34 and dehydrated product 33. Their yields and
enantioselectivities were determined with the results sum-
marized in Table 2. The aldol product 34 was isolated as a
single isomer (vide infra). The enantiomeric excess of aldol
product 34 is a little lower than that of dehydrated product 33
except for the reaction in Et2O. When Et2O, MeOH, and
CH2Cl2 were used as solvents, the enantioselectivity was
moderate. In polar solvents such as DMF and NMP, better
enantioselectivity was achieved. Especially good results were
obtained in NMP. The aldol reaction is fast, and within 1.5 h,
the aldol product 34 and dehydrated product 33 were obtained
in 35 and 42% yield with 76 and 85% ee, respectively (Table
2, entry 6). When the reaction was performed for a long time
(48 h), dehydration proceeded completely, affording 33 in
excellent yield (96%) with good enantioselectivity (85% ee,
Table 2, entry 7).
The relationship between yield and reaction time was
investigated by monitoring the yield and enantiomeric excess
of aldol 34 and dehydrated product 33 at 0.5, 1, 2, 4, 6.5, 18,
21, and 24 h with the results summarized in Figure 2.
The yield of aldol product 34 increases at first and then
gradually decreases as the amount of dehydrated product
increases. The optical purities of the aldol product 34 and
dehydrated product 33 remained almost the same throughout
the reaction. These results indicate that it is probably not the
case that the other diastereomer of the aldol reaction is also
formed but dehydrated instantly but rather that the aldol prod-
uct 34 was obtained selectively and that this dehydrated to
give 33. No kinetic discrimination occurs at the dehydration
stage.
(10) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243. (b) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2000, 122, 9874. (c) Paras, N. A.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2001, 123, 4370. (d) Austin, J. F.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2002, 124, 1172. (e) Northrup, A. B.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2002, 124, 2458. (f) Paras, N. A.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2002, 124, 7894. (g) Brown, S. P.; Goodwin, N.
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M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126,
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Chem., Int. Ed. 2004, 43, 6722. (j) Ouellet, S. G.; Tuttle, J. B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 32. (k) Huang, Y.; Walji, A. M.;
Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051.
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2006, 128, 9328. (m) Lee, S.; MacMillan, D. W. C. Tetrahedron 2006, 62,
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Kirchhoefer, P. J. Am. Chem. Soc. 2003, 125, 2058. (b) Yang, J. W.;
Fonseca, M. T. H.; Vignola, N.; List, B. Angew. Chem., Int. Ed. 2005, 44,
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127, 15036.
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44, 3703. (c) Marigo, M.; Franze´n, J.; Poulsen, T. B.; Zhuang, W.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964. (d) Marigo, M.;
Schulte, T.; Franze´n, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127,
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Brandau, S.; Landa, A.; Franze´n, J.; Marigo, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2006, 45, 4305. (h) Brandau, S.; Maerten, E.; Jørgensen,
K. A. J. Am. Chem. Soc. 2006, 128, 14986. (i) Carlone, A.; Marigo, M.;
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Determination of the Absolute Configuration. The absolute
configuration was determined by chiral HPLC comparison with
an authentic sample prepared as shown in Scheme 2.
The Wieland-Miecher ketone 35 of 73% ee was reduced
with NaBH4 in the presence of CeCl3,17 followed by treatment
with BnBr and NaH, to afford dibenzyl ether 37. Ozonolysis
and then reduction with SmI218 gave keto aldehyde 39. Removal
of the Bn protecting group, followed by an intramolecular aldol
reaction using pyrrolidine, gave bicyclo[4.3.0]nonene derivative
41. Oxidation of alcohol 41 gave ketone 33. HPLC comparison
of this authentic sample with the dehydrated product 33 prepared
using diamine 25‚TFA showed that the two compounds have
the same absolute stereochemistry.
(13) (a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem.,
Int. Ed. 2005, 44, 4212. (b) Gotoh, H.; Masui, R.; Ogino, H.; Shoji, M.;
Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 6853. (c) Hayashi, Y.; Okano,
T.; Aratake, S.; Hazelard, D. Angew. Chem., Int. Ed. 2007, 46, 4922.
The relative stereochemistry of the aldol product 34 was
determined by the NOEs observed in the compounds 43 (Figure
6496 J. Org. Chem., Vol. 72, No. 17, 2007

Organocatalyst-Mediated Asymmetric Aldol Reaction
SCHEME 2. Synthetic Scheme for 33 from the Wieland-Miescher Ketone to Determine the Absolute Configuration of the
Aldol Product
SCHEME 3. Synthetic Scheme of 43
3), which were synthesized as shown in Scheme 3: reduction
of 34 with DIBAL-H afforded a diastereomer mixture of triols
42. Treatment of 42 with 3,5-dinitrobenzoyl chloride in pyridine
afforded bis(3,5-dinitrobenzoyl)ester 43, and the diastereomers
were separated.
with regeneration of the organocatalyst 25‚TFA. The aldol
product 34 was dehydrated to 33 under the reaction conditions
without compromising the enantioselectivity.
In the transition state, a proton coordinated to the nitrogen
of the pyrrolidine ring activates one of the carbonyl groups,
which can occur in the two major conformations A and B shown
in Scheme 4. Although there is considerable steric hindrance
in the case of B, this is avoided in transition state A. Thus, the
reaction proceeds from A to afford 47 stereoselectively.
(14) For another group’s application of diarylprolinol ether, see: (a) Chi,
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Wang, J.; Yu, X.; Wang, W. Tetrahedron Lett. 2006, 47, 5131. (g) Wang,
W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128, 10354. (h) Zhao,
G.-L.; Cordova, A. Tetrahedron Lett. 2006, 47, 7417. (i) Rios, R.; Sunden,
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F.; Barbas, C. F., III. Org. Lett. 2004, 6, 2527.
FIGURE 3. NOE observed for 43B.
Intramolecular Aldol Reaction of 5, 11, and 19. This
intramolecular aldol reaction, in which the aldehyde and ketone
act as nucleophile and electrophile, respectively, was applied
to two other substrates (11 and 19), with the results summarized
in Table 3. With regard to the substituent at the 2 position of
cyclohexadione, not only a methyl group but also propyl and
benzyloxymethyl groups can be successfully utilized to afford
bicyclo[4.3.0]nonene derivatives with good yield and high
enantioselectivities. In the reactions of 11 and 19, the dehydra-
tion reaction was slow, which was performed at room temper-
ature for 1 day.
Reaction Mechanism. The reaction is thought to proceed as
follows: organocatalyst 25‚TFA reacts with the aldehyde moiety
of tricarbonyl 5 to generate enamine 46, which reacts with one
of the carbonyl groups intramolecularly to generate 47. Hy-
drolysis of the iminium ion 47 generates the aldol product 34
(16) (a) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245. (b)
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J. Org. Chem, Vol. 72, No. 17, 2007 6497

Hayashi et al.
SCHEME 4. Reaction Mechanism and Transition State
TABLE 3. Intramolecular Aldol Reaction Catalyzed by 25‚TFAa
and ketone act as nucleophile and electrophile, respectively, a
rare reversal of their normal roles.
Experimental Section
2-Methyl-2-[4-(2-tetrahydropyranyloxy)-2-butenyl]-1,3-cyclo-
hexanedione (2). To a DMF (11.7 mL) solution of 2-methyl-1,3-
cyclohexanedione (393 mg, 3.1 mmol) was added NaH (60% in
oil, 128 mg, 3.2 mmol) at 0 °C, and the reaction mixture was stirred
for 1 h at room temperature. To this reaction mixture was added a
DMF (3 mL) solution of 2-(4-bromobut-2-enyloxy)tetrahydropyran
(1.1 g, 4.1 mmol) over 10 min, and the reaction mixture was stirred
for 5 h at room temperature. The reaction was quenched with a
saturated aqueous NH4Cl solution, the organic materials were
extracted with AcOEt 3 times, and the combined organic phase
was washed with brine 3 times, dried over anhydrous Na2SO4, and
concentrated in vacuo after filtration. Purification by flash column
chromatography (ethyl acetate/hexane ) 1:10) gave 753 mg (86%)
of 2.
1H NMR (400 MHz, CDCl3) δ 1.25 (3H, s), 1.43-1.64 (4H,
m), 1.65-2.10 (4H, m), 2.58 (2H, d, J ) 7.5 Hz), 2.64 (4H, t, J )
6.5 Hz), 3.42-3.60 (1H, m), 3.78-3.94 (1H, m), 4.06 (1H, dd, J
) 12.6, 7.1 Hz), 4.23 (1H, dd, J ) 6.0, 12.5 Hz), 4.61 (1H, s),
5.24-5.38 (1H, m), 5.55-5.75 (1H, m); 13C NMR (100
MHz, CDCl3) δ 17.5, 19.5, 20.1, 25.5, 30.7, 34.7, 38.1 (2C), 62.3,
62.7, 64.8, 98.1, 126.3, 129.9, 209.8 (2C); IR (neat) ν 2942, 1726,
1696, 1119, 1026 cm-1; HRMS (ESI): [M + Na]+: calcd for
C16H24O4Na: 303.1567, found: 303.1579.
2-(4-Hydroxybutyl)-2-methyl-1,3-cyclohexanedione (4). To a
MeOH (270 mL) solution of 2 (8.0 g, 28.5 mmol) was added 10
wt % Pd-C (800 mg) at room temperature, and the reaction mixture
was stirred for 1.5 h under H2 atmosphere. The reaction mixture
was filtrated through a pad of Celite and concentrated in vacuo.
The crude materials of 2-methyl-2-[4-(2-tetrahydropyranyloxy)-
butyl]-1,3-cyclohexanedione were used directly in the next reaction.
To an acetone (70 mL) solution of crude 3 was added 1 N HCl
(28 mL) at room temperature, and the reaction mixture was stirred
for 24 h. The reaction was quenched with pH 7 phosphate buffer,
the organic materials were extracted with AcOEt 3 times, and the
combined organic phase was washed with brine 3 times, dried over
a Reaction was performed employing 11 on a 0.1 mmol scale or 19 on
a 0.05 mmol scale at 0.1 M in NMP. b Isolated yield. c Optical yield was
determined by HPLC on a chiral phase (chiralcel OB-H). d Optical yield
was determined by HPLC on a chiral phase (chiralcel OD-H). e Optical
yield was determined by HPLC on a chiral phase (chiralpak AS-H).
Conclusion
In summary, we have found that the trifluoroacetic acid salt
of 2-(pyrrolidinylmethyl)pyrrolidine (25) is an effective orga-
nocatalyst of the intramolecular aldol reaction of tricarbonyl
compounds 5, 11, and 19 to afford bicyclo[4.3.0]nonene deriv-
atives 33, 44, and 45 with the creation of a quaternary carbon
center with high enantioselectivity. In this reaction, the aldehyde
6498 J. Org. Chem., Vol. 72, No. 17, 2007

Organocatalyst-Mediated Asymmetric Aldol Reaction
anhydrous Na2SO4, and then concentrated in vacuo after filtration.
Purification by flash column chromatography (ethyl acetate/hexane
) 1:10) gave 3.7 g (65% over two steps) of 4.
organic phase was washed with brine solution 3 times, dried over
anhydrous Na2SO4, and concentrated in vacuo after filtration.
Purification by preparative thin layer chromatography (ethyl acetate/
hexane ) 1:1) gave 42.6 mg (89%) of 33.
(S)-7-(1-Methyl-2-oxo-bicyclo[4.3.0]non-6-ene)carbaldehyde
(33). 1H NMR (400 MHz, CDCl3) δ 1.35 (3H, s), 1.56-1.70 (1H,
m), 1.72-1.81 (1H, m), 2.18-2.33 (2H, m), 2.40-2.56 (4H, m),
2.65-2.78 (1H, m), 3.26-3.36 (1H, m), 9.98 (1H, s); 13C
NMR (100 MHz, CDCl3) δ 22.8, 23.8, 24.0, 26.4, 30.4, 37.8, 63.8,
136.1, 165.2, 187.8, 211.4; IR (neat) ν 2960, 2869, 1713, 1665,
1635, 1346, 1190 cm-1; HRMS (ESI): [M + Na]+: calcd for
C11H14O2Na: 201.0886, found: 201.0890; [R]D22.6 +83.2 (c ) 0.16,
MeOH).
1H NMR (400 MHz, CDCl3) δ 1.10-1.24 (2H, m), 1.20 (3H,
s), 1.42-1.58 (2H, m), 1.72-1.81 (2H, m), 1.81-2.04 (2H, m),
2.21-2.40 (1H, bs), 2.54-2.75 (4H, m), 3.57 (2H, t, J ) 6.4
Hz); 13C NMR (100 MHz, CDCl3) δ 17.5, 19.7, 21.0, 32.5, 36.6,
37.9 (2C), 62.1, 65.5, 210.6 (2C); IR (neat) ν 3403, 2941, 1724,
1694, 1462, 1027 cm-1; HRMS (ESI): [M + Na]+: calcd for
C11H18O3Na: 221.1148, found: 221.1141.
(3-Formylpropyl)-2-methyl-1,3-cyclohexanedione (5). To a
DMSO (8 mL) solution of 4 (400 mg, 2.0 mmol) was added IBX
(o-iodoxybenzoic acid, 1.6 g, 6.0 mmol) at room temperature, and
the reaction mixture was stirred for 1.5 h at the same temperature.
The reaction was quenched with a saturated aqueous NaHCO3
solution, the organic materials were extracted with AcOEt 3 times,
and the combined organic phase was washed with additional
saturated aqueous NaHCO3 solution 3 times, dried over anhydrous
Na2SO4, and concentrated in vacuo after filtration. Purification by
flash column chromatography (ethyl acetate/hexane ) 1:3) gave
144 mg (37%) of 5.
Enantiomeric excess was determined by HPLC with a Chiralcel
OB-H column (10:1 ) hexane/2-propanol), 1.0 mL/min; major
enantiomer tr ) 18.9 min, minor enantiomer tr ) 26.4 min.
(1S,6S,9S)-9-(1-Hydroxy-6-methyl-5-oxo-bicyclo[4.3.0]nonane)-
1
carbaldehyde (34). H NMR (400 MHz, CDCl3) δ 1.19 (3H, s),
1.54-1.70 (3H, m), 1.83-2.13 (4H, m), 2.15-2.23 (1H, m), 2.26-
2.33 (1H, m), 2.50-2.68 (3H, m), 9.74 (1H, d, J ) 1.6 Hz); 13C
NMR (100 MHz, CDCl3) δ 17.9, 20.4, 20.7, 30.0, 31.3, 36.7, 55.0,
62.4, 85.4, 204.1, 212.2; IR (neat) 3483, 2944, 1704, 1463, 991
cm-1; HRMS (ESI): [M + Na]+: calcd for C11H16O3Na: 219.0992,
1H NMR (400 MHz, CDCl3) δ 1.26 (3H, s), 1.45 (2H, dtt, J )
4.4, 7.2, 14.4 Hz), 1.76-1.84 (2H, m), 1.87-2.04 (2H, m), 2.42
(2H, dt, J ) 1.2, 7.2 Hz), 2.61-2.75 (4H, m), 9.72 (1H, t, J ) 0.8
Hz); 13C NMR (100 MHz, CDCl3) δ 17.5, 17.6, 20.4, 35.7, 38.0
(2C), 43.7, 65.4, 201.5, 210.0 (2C); IR (neat) ν 2943, 2730, 1723,
1694, 1459, 1027 cm-1; HRMS (ESI): [M + Na]+: calcd for
C11H16O3Na: 219.0992, found: 219.0997.
Typical Procedure for the Intramolecular Aldol Reaction
(Table 3, entry 1). To a NMP (N-methyl-2-pyrrolidinone, 2.7 mL,
0.1 M) solution of aldehyde 5 (54.5 mg, 0.27 mmol) was added a
TFA salt of 25 (21.7 mg, 30 mol %) at 0 °C, and the reaction
mixture was stirred for 56 h at the same temperature. The reaction
was quenched with pH 7 phosphate buffer solution, the organic
materials were extracted with AcOEt 3 times, and the combined
22.0
found: 219.0984; [R]D -19.6 (c ) 0.18, MeOH).
Acknowledgment. This work was partially supported by the
Toray Science Foundation and a Grant-in-Aid for Scientific
Research from MEXT. We thank Dr. Hiroyuki Koshino at
RIKEN for the determination of the relative configuration of
43B.
Supporting Information Available: Copies of 1H and 13C NMR
and IR of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0709100
J. Org. Chem, Vol. 72, No. 17, 2007 6499